Activities of the principal brain vesicular monamine transporter, VMAT2, are key to understanding the cellular compartmentalization of monoamines. They may play key roles in modulating the actions and neurotoxicities induced by amphetamine and by each of the toxins that selectively kills dopaminergic neurons to provide the best current models of Parkinsons disease. Studies of this gene are thus of interest for a variety of human disorders and drug responses. They could even play roles in normal age-related alterations in these systems. In this year, workers in this Branch continued to describe the poperties of knockout mice with deletions of the VMAT2 gene and other plasma membrane monoamine transporters and obtained initial data from mice with combined deletions of VMAT2 and overexpression of synuclein. Aging studies documented clear reductions in locomotion, in amphetamine responsiveness and exaggerated age-related losses of dopaminergic markers in the heterozygous VMAT2 knockouts with apparent synergistic interactions with synuclein in initial studies. Mice with deletions of VMAT2 and the plasma membrane transporters for DAT and SERT are viable and display interesting alterations in amphetamine responses. VMAT2 knockout mice continue to substantially enhance our understanding of mechanisms of age- related alterations in dopaminergic systems and actions of psychostimulants and locomotor systems. Studies on the common haplotypes in the human VMAT2 gene continued with analyses of the epigenetic influences, as well as the influences of haplotypes, on the human expression of the gene. Assays developed and validated during this year allow assessment of haplotype and promoter region methylation in unrelated individuals, correlating well with indivdiual differences in drug responses. Work begun during this year seeks individual differences in methylphenidate responses (rewarding, positive feelings)in relation to VMAT2 haplotypes.